The overall goal of this biomedical research partnership is to couple cancer imaging and therapy using nanoparticles that provide ultrasonic activation, multimodality imaging, and efficient and stable drug transport. These methods enable efficacious drug delivery with minimal systemic toxicity in the treatment of multifocal and metastatic cancers, and in particular in melanoma, head and neck, prostate, and breast tumors. There is great momentum for image-guided interventions in general and image-guided drug delivery in particular, with many activatable particles under development. In our first grant cycle, we established the feasibility of ultrasound drug delivery to tumors, demonstrating that we can: target a significant fraction of drug carrying particles to tumors (averaging 20% of the injected dose per cubic centimeter of tissue following systemic administration), obtain a high (up to 33 dB) target-to-background ratio image of the vehicles within the cancerous lesion, image tumors with a diameter of 4 mm or greater, achieve at least a 50-fold increase in drug delivery to tumors (as compared with systemic administration of free model drugs), and demonstrate a therapeutic response in vivo with the combination of ultrasound and liposomal cisplatin in as little as 24 hours. We have also created ultrasound infrastructure for imaging and therapy, embedding therapeutic capabilities within the clinical ultrasound system of our partner Siemens Medical Solutions, creating a positron emission tomography (PET) labeling method for liposomes, synthesizing a near-infrared probe, and cross-validating these components. Our ultrasound imaging and therapy system can operate independently or in combination with PET and computed tomography (CT). The primary goal for this renewal is to establish efficacious infrastructure and protocols for ultrasound-enhanced particle-based drug delivery for the treatment of primary and metastatic tumors. In order to accomplish this goal we will create a combined PET-CT-US system for image-guided-interventions, optimize the 3D-ultrasound heating protocol, maximize the target-to-background ratio for guiding interventions with PET-CT-US, finalize the loading and formulation for an activatable cisplatin liposome and evaluate ultrasound-enhanced intravenous therapy under PET-CT guidance.